Directly compressible formulations of azithromycin

ABSTRACT

The present invention relates to a dry blend, used for forming azithromycin tablets by direct compression, comprising non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient. This invention also relates to an azithromycin tablet comprising non-dihydrate azithromycin and at least one pharmaceutically acceptable excipient. Preferably, the azithromycin tablet is formed by directly compressing the dry blend, of the present invention, to form said azithromycin tablet. Preferably, the azithromycin tablet, of the present invention, contains a dosage of 250 mgA, 500 mgA or 600 mgA of azithromycin. This invention further relates to an azithromycin tablet which is produced by forming a dry blend of a non-granulated azithromycin form A and at least one pharmaceutically acceptable excipient. The azithromycin tablet is then formed by directly compressing the dry blend.

BACKGROUND OF THE INVENTION

Direct compression is a tableting process in which tablets arecompressed directly from powder blends containing an active ingredient.In direct compression, all the ingredients required for tableting,including the active ingredient and processing aids, are incorporatedinto a free flowing blend which is then tableted. The active ingredient,excipients, and other substances are blended and then compressed intotablets. Tablets are typically formed by pressure being applied to amaterial in a tablet press.

There are a number of tablet presses, each varying in productivity anddesign but similar in basic function and operation. All compress atablet formulation within a die cavity by pressure exerted between twosteel punches, a lower punch and an upper punch.

Pharmaceutical manufacturers prefer the use of direct compression, overwet and dry granulation processes, because of its shorter processingtimes and cost advantages. However, direct compression is generallylimited to those situations in which the active ingredient has physicalcharacteristics suitable for forming pharmaceutically acceptabletablets.

Some active ingredients, which are generally unsuitable for directcompression, can be formed into a directly compressible formulation byincorporating one or more excipients before compressing. The addition ofexcipients to the formulation, however, will increase the tablet size ofthe final product. As tablet size must be within certain parameters tofunction as a suitable dosage form, there is a limit beyond whichincreasing tablet size to accommodate increasing amounts of excipientsto enhance compactability is not practical. As a result, manufacturersare often limited to using the direct compression method forformulations containing a low dose of the active ingredient percompressed tablet such that the formulation may accommodate sufficientlevels of excipient to make direct compression practical.

In the development of pharmaceutical dosage forms, it is important tobalance several different objectives. Preparation of a pharmaceuticaldosage form should be economical. Also, the dosage form should be easyto swallow. Further, smaller dosage forms are more acceptable topatients and result in improved patient compliance.

It is known that, to form a tablet from a given formulation, theformulation must have good flow properties for precise volumetricfeeding of the material to the die cavity and suitable compressibility,compactability, and ejection properties to form a tablet. The flowproperties of powders are critical for efficient tableting operation.The ability of the material to flow freely into the die is important toensure that there is uniform filling of the die and a continuousmovement of the material from its source. Poor flow properties of thematerial will affect the weight, hardness and friability of the tablets.Good flow of powders, to be compressed, is necessary to assure efficientmixing and acceptable weight uniformity for the compressed tablets.

Azithromycin, which is also named9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A, generally, is notconsidered to be amenable to the production of directly compressibletablets of azithromycin formulations.

It would be desirable to develop an azithromycin formulation that isamenable to direct compression and that produces tablets havingacceptable hardness and friability.

SUMMARY OF THE INVENTION

The present invention relates to a dry blend, used for formingazithromycin tablets by direct compression, comprising non-dihydrateazithromycin and at least one pharmaceutically acceptable excipient.

This invention also relates to an azithromycin tablet comprisingnon-dihydrate azithromycin and at least one pharmaceutically acceptableexcipient. Preferably, the azithromycin tablet is formed by directlycompressing the dry blend, of the present invention, to form saidazithromycin tablet.

Preferably, the azithromycin tablet, of the present invention, containsa dosage of 250 mgA, 500 mgA or 600 mgA of azithromycin.

This invention further relates to an azithromycin tablet which isproduced by forming a dry blend of a non-granulated azithromycin form Aand at least one pharmaceutically acceptable excipient. The azithromycintablet is then formed by directly compressing the dry blend.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the bulk particle size distribution of azithromycinfor azithromycin lots 1 through 11 by light scattering analysis (MalvernMastersizer S, Malvern Instruments, Worcestershire, UK).

As used in FIG. 1:

-   The -Δ- symbol represents the particle size distribution of bulk lot    1-   The -x- symbol represents the particle size distribution of bulk lot    2-   The -♦- symbol represents the particle size distribution of bulk lot    3-   The -⋄- symbol represents the particle size distribution of bulk lot    4-   The -▪- symbol represents the particle size distribution of bulk lot    5-   The -▴- symbol represents the particle size distribution of bulk lot    6-   The . . . ⋄ . . . symbol represents the particle size distribution    of bulk lot 7-   The . . . Δ . . . symbol represents the particle size distribution    of bulk lot 8-   The . . . □ . . . symbol represents the particle size distribution    of bulk lot 9-   The . . . - . . . symbol represents the particle size distribution    of bulk lot 10-   The    symbol represents the particle size distribution of bulk lot 11

DETAILED DESCRIPTION

In the specification and claims that follow, reference will be made to anumber of terms which shall be defined to have the following meaning.

The term “dry blend”, as used herein, means a generally homogeneousmixture of two or more materials in particle form. The particles may bein powdered form or, alternatively, larger aggregated or agglomeratedparticles.

The term “azithromycin” as used herein includes all crystalline andamorphous forms of azithromycin, including all polymorphs, isomorphs,clathrates, salts, solvates and hydrates of azithromycin, unlessspecifically stated. Azithromycin forms include the dihydrate form andvarious non-dihydrate forms.

The stable dihydrate of azithromycin, which is essentiallynon-hygroscopic under conditions of relative humidity conducive toformulation of azithromycin and is disclosed in U.S. Pat. No. 6,268,489,is designated herein as “form A”. The form is a crystalline dihydrate,prepared by crystallization from tetrahydrofuran and an aliphatic(C₅-C₇) hydrocarbon in the presence of at least two molar equivalents ofwater.

“Non-dihydrate azithromycin” means all amorphous and crystalline formsof azithromycin including all polymorphs, isomorphs, clathrates, salts,solvates and hydrates of azithromycin other than form A, the dihydrateform of azithromycin (azithromycin dihydrate).

Non-dihydrate azithromycin includes a hygroscopic hydrate ofazithromycin, as disclosed in U.S. Pat. No. 4,474,768, which isdesignated herein as “form B”.

Azithromycin may be present in several alternate crystallinenon-dihydrate forms, including forms D, E, F, G, H, J, M, N, O, P, Q andR, which are disclosed in U.S. patent application Ser. No. 10/152,106,filed 21 May 2002, the teachings of which are incorporated herein, byreference, in their entirety.

Both Family I and Family II isomorphs are hydrates and/or solvates ofazithromycin. The solvent molecules in the cavities have a tendency toexchange between solvent and water under specific conditions. Therefore,the solvent/water content of the isomorphs may vary to a certain extent.Forms B, F, G, H, J, M, N, O, and P belong to Family I azithromycin andbelong to a monoclinic P2₁ space group with cell dimensions ofa=16.3±0.3 ∈, b=16.2±0.3 ∈, c=18.4±0.3 ∈ and beta=109±2°. Forms D, E andR belong to Family II azithromycin and belong to an orthorhombic P2₁2₁2₁ space group with cell dimensions of a=8.9±0.4 ∈, b=12.3±0.5 ∈ andc=45.8±0.5 ∈. Form Q is distinct from Families I and II.

Form D azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.C₆H₁₂ in itssingle crystal structure, being azithromycin monohydrate monocyclohexanesolvate. Form D is further characterized as containing 2-6% water and3-12% cyclohexane by weight in powder samples. From single crystal data,the calculated water and cyclohexane content of form D is 2.1 and 9.9%,respectively.

Form E azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.C₄H₈O beingazithromycin monohydrate mono-tetrahydrofuran solvate. Form E is amonohydrate and mono-THF solvate by single crystal analysis.

Form G azithromycin is of the formula C₃₈H₇₂N₂O₁₂.1.5H₂O in the singlecrystal structure, being azithromycin sesquihydrate. Form G is furthercharacterized as containing 2.5-6% water and <1% organic solvent(s) byweight in powder samples. The single crystal structure of form Gconsists of two azithromycin molecules and three water molecules perasymmetric unit. This corresponds to a sesquihydrate with a theoreticalwater content of 3.5%. The water content of powder samples of form Granges from about 2.5 to about 6%. The total residual organic solvent isless than 1% of the corresponding solvent used for crystallization.

Form H azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.0.5C₃H₈O₂ beingazithromycin monohydrate hemi-1,2 propanediol solvate. Form H is amonohydrate/hemi-propylene glycol solvate of azithromycin free base.

Form J azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.0.5C₃H₇OH in thesingle crystal structure, being azithromycin monohydrate hemi-n-propanolsolvate. Form J is further characterized as containing 2-5% water and1-5% 1-propanol by weight in powder samples. The calculated solventcontent is about 3.8% n-propanol and about 2.3% water.

Form M azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.0.5C₃H₇OH, beingazithromycin monohydrate hemi-isopropanol solvate. Form M is furthercharacterized as containing 2-5% water and 1-4% 2-propanol by weight inpowder samples. The single crystal structure of form M would be amonohydrate/hemi-isopropranolate.

Form N azithromycin is a mixture of isomorphs of Family I. The mixturemay contain variable percentages of isomorphs, F, G, H, J, M and others,and variable amounts of water and organic solvents, such as ethanol,isopropanol, n-propanol, propylene glycol, acetone, acetonitrile,butanol, pentanol, etc. The weight percent of water can range from1-5.3% and the total weight percent of organic solvents can be 2-5% witheach solvent content of 0.5 to 4%.

Form O azithromycin is of the formula C₃₈H₇₂N₂O₁₂.0.5H₂O.0.5C₄H₉OH,being a hemihydrate hemi-n-butanol solvate of azithromycin free base bysingle crystal structural data.

Form P azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.0.5C₅H₁₂O beingazithromycin monohydrate hemi-n-pentanol solvate.

Form Q azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.0.5C₄H₈O beingazithromycin monohydrate hemi-tetrahydrofuran solvate. It contains about4% water and about 4.5% THF.

Form R azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.C₅H₁₂O beingazithromycin monohydrate monomethyl tert-butyl ether solvate. Form R hasa theoretical water content of 2.1 weight % and a theoretical methyltert-butyl ether content of 10.3 weight %.

Form F azithromycin is of the formula C₃₈H₇₂N₂O₁₂.H₂O.0.5C₂H₅OH in thesingle crystal structure, being azithromycin monohydrate hemi-ethanolsolvate. Form F is further characterized as containing 2-5% water and1-4% ethanol by weight in powder samples.

The single crystal of form F is crystallized in a monoclinic spacegroup, P2₁, with the asymmetric unit containing two azithromycins, twowaters, and one ethanol, as a monohydrate/hemi-ethanolate. It isisomorphic to all Family I azithromycin crystalline forms. Thetheoretical water and ethanol contents are 2.3 and 2.9%, respectively.

The term “non-granulated” azithromycin, as used herein, means that theazithromycin is not dry granulated, such as by slugging or rollercompaction, or wet granulated.

“Bulk azithromcyin”, as used herein, means azithromycin particleswithout added excipients.

The term “pharmaceutically acceptable” means that which is generallysafe, non-toxic and neither biologically nor otherwise undesirable andincludes that which are acceptable for veterinary use as well as humanpharmaceutical use.

The phrase “directly compressible formulation” means a formulation whichcan be compressed into a pharmaceutically acceptable tablet without aprior granulation step.

The term “compressibility” means the degree to which a formulationdecreases in volume when air is removed.

The term “compactibility” means the ease with which a formulation iscompressed into tablets possessing acceptable hardness properties.

The term “free flowing” as used herein means the ability of material toflow without mechanical agitation on standard tableting equipmentutilizing gravity to induce flow, such as an F-press. Good flowingmaterials result in dosage forms with good weight uniformity asevidenced by low relative standard deviation (% RSD) or coefficient ofvariation (% CV) of dosage form weight.

The term “fines” as used herein refers to particles with a diameter ofless than about 44 microns, as measured by the Malvern method.

The term “F-press” as used herein refers to a MANESTY F-PRESS (ManestyMachines Ltd., UK).

The term “mgA” refers to milligrams of the free base of azithromycin.

In the method of the present invention, the azithromycin used may bemilled or unmilled bulk drug.

The dry blend, of the present invention, is used to producenon-dihydrate azithromycin tablets by direct compression. Typically, thedry blend contains from about 1% to about 80% of non-dihydrateazithromycin. Preferably, the azithromycin, in the dry blend, isnon-granulated.

It is also preferred that the azithromycin in the dry blend comprise aform of non-dihydrate azithromycin selected from forms B, D, E, F, G, H,J, M, N, O, P, Q, R, or mixtures thereof.

In addition to the non-dihydrate azithromycin, the dry blend of thepresent invention, also includes at least one pharmaceuticallyacceptable suitable excipient. The excipients may include processingaids that improve the direct compression tablet-forming properties ofthe dry blend.

In one embodiment of the present invention, the dry blend is suitablefor use in forming azithromycin tablets through gravity-fed, directcompression tableting.

To be suitable for direct compression on a gravity fed tableting press,particularly at higher azithromycin loadings, such as 45% or more, theparticle size profile of azithromycin, is critical. As azithromycinloading increases, the fines in the bulk azithromycin tend to furtherdegrade the flow properties of the dry blend as they constitute a higherpercentage of the total particles within the dry blend. Therefore, it isnecessary to reduce the amount of azithromycin fines within the dryblend to obtain acceptable flow on a gravity fed tableting press andmake a tablet having acceptable friability.

By “gravity fed tableting press” it is meant that a pharmaceuticalformulation is not force fed into a die, and that the flow of thepharmaceutical formulation is induced by gravity. An example of agravity fed tableting press is the Manesty F-press.

In this embodiment of the present invention, the particle sizedistribution was determined using a Malvern Mastersizer S (MalvernInstruments, Worcestershire, UK) with a MS-1-Small Volume SampleDispersion Unit. This unit allowed for particle size analysis through awet sample dispersion step and subsequent particle size measurementsusing laser diffraction.

In this embodiment of the present invention, to achieve suitable flowproperties for the dry blend, particularly at higher azithromycinloadings, typically, less than about 20% of the azithromycin particles,by volume, in the dry blend, should have a diameter of 44 μm or less.Preferably, less than about 14% of the azithromycin particles shouldhave a diameter of 44 μm or less.

Likewise, in the present dry blend, it is preferred that less than about27% of the azithromycin particles should have a diameter of 74 μm orless.

Further, in the present dry blend, it is preferred that less than about60% of the azithromycin particles should have a diameter of 105 μm orless. More preferably less than about 50% of the azithromycin particlesshould have a diameter of 105 μm or less.

Even more preferably, less than about 6% of the azithromycin particlesshould have a diameter of 16 μm or less.

In a more preferred embodiment of the present invention, the dry blendcontains less than about 6% of the azithromycin particles, by volume,with a diameter of about 16 μm or less, and less than about 20% of theazithromycin particles, by volume, with a diameter of about 44 μm orless. Even more preferably, less than about 14% of the azithromycinparticles should have a diameter of 44 μm or less.

In an even more preferred embodiment, the dry blend contains less thanabout 6% of the azithromycin particles, by volume, with a diameter ofabout 16 μm, or less, less than about 20% of the azithromycin particles,by volume, with a diameter of about 44 μm, or less, and less than about27% of the azithromycin particles, by volume, with a diameter of about74 μm or less. Even more preferably, less than about 14% of theazithromycin particles should have a diameter of 44 μm or less.

In yet an even more preferred embodiment, the dry blend contains lessthan about 6% of the azithromycin particles, by volume, with a diameterof about 16 μm, or less, less than about 20% of the azithromycinparticles, by volume, with a diameter of about 44 μm, or less, less thanabout 27% of the azithromycin particles, by volume, with a diameter ofabout 74 μm, or less, and less than about 60% of the azithromycinparticles, by volume, with a diameter of about 105 μm or less. Even morepreferably, less than about 14% of the azithromycin particles shouldhave a diameter of 44 μm, or less, and less than about 50% of theazithromycin particles should have a diameter of 105 μm or less.

The flow properties of a dry blend may be evaluated by a number ofmethods known in the art. One way of characterizing formulationproperties of a powdered material is by bulk density measurements. Asimple method to provide a description of flow characteristics by bulkdensity measurement is Carr's Compressibility Index (Carr's Index).

Carr's Compressibility Index is a simple test to evaluate flowability bycomparing both the initial and final (tapped) densities and the rate ofpacking down. A useful empirical guide to flow is given by Carr'scompressibility index:Compressibility Index(%)=[(tapped density−initial density)/tappeddensity]×100

In the present invention, it was found that the Carr's CompressibilityIndex of the dry blend provided a good indication of the flowcharacteristics and thus, the suitability for using the dry blend toprepare tablets through gravity-fed, direct compression tableting.Generally, it was observed that formulations with Carr's CompressibilityIndex values of less than about 34% resulted in acceptable flow andtabletability on an F-press, whereas formulations with values of 34%, ormore, resulted in poor flow and an inability to form suitable tablets onan F-press. Therefore, in the present invention, the dry blend shouldhave a Carr's Compressibility Index less than about 34%, more preferablyless than about 31%, and even more preferably less than about 28%.

Another measurement of particle flow is the internal angle of frictionthat may be determined by shear cell experiments. The primary differencein the flow behavior of liquids and powders is in their internalfriction. The lack of internal friction of liquids allows them to formlevel surfaces at rest, while internal friction in powders allows theformation of heaps or other non-level surfaces.

Internal friction of powders is typically characterized using a shearcell, which is a device that places a powder sample under known physicalstress conditions and measures its response to those stresses, asdisclosed in “Some Measurements of Friction in Simple Powder Beds”,Heistand, E. N. and Wilcox, C. J. (J. Pharm. Sci. 57 (1968) 1421),incorporated herein by reference. The response is reported as an angleof internal friction. This parameter is a characteristic of the powdersmeasured and varies between materials. The lower the value of the angleof internal friction, the better flowing the powder is. This parametermay be used as a predictor of tablet weight variation during tabletingoperations, since the powder fill weight, and therefore the tabletweight, is dependent on the ability of the powder to quickly flow intothe tableting die. In the present invention, dry blends, suitable foruse in the preparation of tablets by direct compression, had angles ofinternal friction of less than about 34°, and more preferably less thanabout 31°.

Even more preferably, dry blends of the present invention have a Carr'sCompressibility Index of less than about 34% and an internal angle offriction of less than about 34°.

Most preferably, dry blends of the present invention have a Carr'sCompressibility Index of less than about 28% and an internal angle offriction of less than about 31°.

A dry blend, having properties within the aforementioned ranges, may beachieved by methods including, but not limited to, providing suitableexcipients, by increasing particle size, or by modifying processingconditions. Typically, addition of excipients provides a means to modifythe flow profile of a low dose pharmaceutical formulation, ascommercially available excipients have good flow properties. For dryblends, having higher azithromycin loadings, Carr's CompressibilityIndex and/or internal angles of friction with the aforementioned rangesmay be achieved by obtaining the azithromycin particle size distributiondiscussed above.

Accordingly, the particle size profile of the azithromycin should beevaluated, and if necessary, the azithromycin should be processed toachieve the particle size profile.

To produce azithromycin particles having the desired particle sizedistribution, the bulk azithromycin may be further processed by methodsincluding, but not limited to, 1) milling 2) screening 3)recrystallization and 4) granulation, including dry and wet granulation.The aforementioned further processing methods may be used alone or incombination.

Milling involves subjecting the drug to a shear force such that theparticle size of the drug is reduced. The milling may be an aggressiveprocess where the particle size is reduced significantly, or it may be anon-aggressive process where the particle size is not reducedsignificantly, but merely done to delump or break up larger clumps ofdrug formed in the bulk drug.

In the pharmaceutical industry, milling is often used to reduce theparticle size of solid materials. Many types of mills are availableincluding pin mills, hammer mills and jet mills. One of the mostcommonly used types of mill is the hammer mill. The hammer mill utilizesa high-speed rotor to which a number of fixed or swinging hammers areattached. The hammers can be attached such that either the knife face orthe hammer face contacts the material. As material is fed into the mill,it impacts on the rotating hammers and breaks up into smaller particles.A screen is located below the hammers, which allows the smallerparticles to pass through the openings in the screen. Larger particlesare retained in the mill and continue to be broken up by the hammersuntil the azithromycin particles are fine enough to flow through thescreen.

The azithromycin particles may optionally be screened. In screening,bulk drug is placed through a mesh screen or series of mesh screens toobtain the desired particle size for the bulk drug.

Several methods are known for increasing the particle size of drugs,including, but not limited to, granulation and recrystallization. Wetgranulation, for example, involves the use of a granulating liquid thatcauses the azithromycin particles to agglomerate and thus increase theparticle size. Suitable wet granulation methods for the preparation ofazithromycin particles are disclosed in copending U.S. ProvisionalApplication Ser. No. 60/343,469, titled “Methods for Wet GranulatingAzithromycin”, filed Dec. 21, 2001 and in copending International.Application Docket Number PC23065A titled “Methods for Wet GranulatingAzithromycin”. Suitable methods for dry granulating azithromycinparticles are disclosed in copending U.S. Provisional Application Ser.No. 60/354,041, titled “Dry Granulated Formulations of Azithromycin”,filed Feb. 1, 2002.

In the present invention, wet granulation of the bulk drug without theuse of additional excipients may be used to increase the particle sizeof the material

Recrystallization involves dissolving a bulk drug and allowing it toreform as new crystals which are adequate in particle size for the usein an azithromycin direct compression tablet.

Another method to increase the particle size is to sieve the bulk drugto remove the smaller particles.

While it was found that the azithromycin particle size distribution wasimportant for achieving acceptable flow properties on gravity fedtableting equipment, dry blends with lower azithromycin loadings or withan undesirable amount of fines may still be directly compressed to formtablets by adjusting the processing conditions, equipment and/orexcipients as necessary. For example, a dry blend with a higher amountof fines may be tableted, by direct compression, through using forcedfed tableting equipment. Methods of assisting flow, or force feeding,are well known in the art.

Thus, in an alternative embodiment of the present invention, anon-dihydrate azithromycin dry blend can be mechanically processed in amanner to compensate for poor flow properties. For example, the materialmay be introduced into the die using a mechanical force feeder. Amechanical force feeder might be used when poor weight control isobtained using a pharmaceutical formulation. Further, the flowproperties of a dry blend may also be modified by decreasing thepercentage of bulk azithromycin in the dry blend.

The amount of azithromycin and of the additional excipients andprocessing aids may be varied provided suitable direct compressibilityproperties of the pharmaceutical formulation are achieved, as defined byflow measurements such as Carr's Compressibility Index and internalangle of friction as described herein.

Any additional excipients, such as diluent or dry binder shouldpreferably have good flow characteristics and compactibility. Excipientshaving good flow properties are readily available.

In the dry blend, of the present invention, excipients suitable for usein direct compression include, but are not limited to, binders,diluents, disintegrants, lubricants, fillers, carriers, and the like.

Binders are used to impart cohesive qualities to a tablet formulation,and thus ensure that a tablet remains intact after compaction. Suitablebinder materials include, but are not limited to, microcrystallinecellulose, gelatin, sugars (including sucrose, glucose, dextrose andmaltodextrin), polyethylene glycol, waxes, natural and synthetic gums,polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethylcellulose, and the like).

Lubricants can be employed herein in the manufacture of certain dosageforms, and will usually be employed when producing tablets. In thepresent invention, a lubricant is added just before the tableting step,and is mixed with the formulation for a minimum period of time to obtaingood dispersal. The lubricant employed in a composition of the presentinvention may be one or more compounds. Examples of suitable lubricantsinclude, but are not limited to, magnesium stearate, calcium stearate,zinc stearate, stearic acid, talc, glyceryl behenate, polyethyleneglycol, polyethylene oxide polymers (for example, available under theregistered trademarks of Carbowax™ for polyethylene glycol and Polyox™for polyethylene oxide from Dow Chemical Company, Midland, Mich.),sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodiumstearyl fumarate, DL-leucine, colloidal silica, and others as known inthe art. Preferred lubricants are magnesium stearate, calcium stearate,zinc stearate and mixtures of magnesium stearate with sodium laurylsulfate. Lubricants may comprise from about 0.25% to about 10% of thetablet weight, more preferably from about 0.5% to about 3%.

Disintegrants are used to facilitate tablet disintegration or “breakup”after administration, and are generally starches, clays, celluloses,algins, gums or crosslinked polymers. Suitable disintegrants include,but are not limited to, crosslinked polyvinylpyrrolidone (PVP-XL),sodium starch glycolate, and croscarmellose sodium. If desired, thepharmaceutical formulation may also contain minor amounts of nontoxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents and the like, for example, sodium acetate, sorbitan monolaurate,triethanolamine sodium acetate, triethanolamine oleate, sodium laurylsulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fattyacid esters, etc.

The diluent employed in a composition of the present invention may beone or more compounds which are capable of providing compactibility andgood flow. A variety of materials may be used as fillers or diluents.Suitable diluents or fillers include, but are not limited to, lactose(monohydrate, spray-dried monohydrate, anhydrous and the like), sucrose,dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystallinecellulose; Avicel®, FMC Biopolymer, Philadelphia, Pa.), dihydrated oranhydrous dibasic calcium phosphate, calcium carbonate, calcium sulfate,and others as known in the art. More preferably, free-flowing diluentswhich can improve blend flow are: spray-dried lactose monohydrate (suchas 316 Fast Flo®, Foremost Farms, Baraboo, Wis. and Phamatose® DCL 11,DMV International Pharma, Veghel, The Netherlands), agglomeratedfree-flowing lactose monohydrate (such as Tablettose®, Meggle GMBH,Wasserburg, Germany), granulated lactose monohydrate (such asPharmatose® DCL 15, DMV International Pharma, Veghel, The Netherlands),roller dried lactose monohydrate (such as Pharmatose® DCL 21, DMVInternational Pharma, Veghel, The Netherlands), direct compressionlactose, anhydrous (such as Pharmatose® DCL 40, DMV InternationalPharma, Veghel, The Netherlands and Anhydrous DT Lactose, QuestInternational Inc., Hoffman Estates, Ill.), spray-dried lactose withmicrocrystalline cellulose (MicroLac® 100, Meggle GMBH, Wasserburg,Germany), spray-dried lactose with cellulose (Cellactose®, Meggle GMBH,Wasserburg, Germany), direct compression sucrose (such as Sugartab®,Penwest Pharmaceuticals Co., Patterson, N.Y. and Nu-Tab®, DMVInternational Pharma, Veghel, The Netherlands), co-crystallized sucroseand modified dextrins (Di-Pac®, DominoSpecialty Ingredients, Baltimore,Md.), spray-dried dextrates (Emdex®, Penwest Pharmaceuticals Co.,Patterson, N.Y.), coarse dextrose (such as Cerelose® Coarse Dextrose2037, Corn Products International, Inc., Westchester, Ill.),agglomerated dextrose (such as Unidex® 2034, Corn ProductsInternational, Inc., Westchester, Ill.), spray-dried maltodextrin (suchas Maltrin® M 510, Grain Processing Corp., Muscatine, Iowa), finegranular maltodextrin (such as Maltrin® M 150, Grain Processing Corp.,Muscatine, Iowa), spray-dried maltose (Advantose™ 100 Maltose Powder,SPI Pharma, New Castle, Del.), spray-dried mannitol (such as Mannogem™EZ Spray Dried Mannitol, SPI Pharma, New Castle, Del. and Parteck™ M, EMIndustries, Inc., Hawthorne, N.Y.), granular mannitol (such as MannitolGranular 2080, SPI Pharma, New Castle, Del. and Mannitol Granular, SPIPharma, New Castle, Del.), spray-dried sorbitol (such as Parteck™ SI[Sorbitol Instant™], EM Industries, Inc., Hawthorne, N.Y.), coarsesorbitol (such as grades 834, 2016 and 1162 Crystalline Sorbitol, SPIPharma, New Castle, Del.), direct compression fructose co-dried withstarch (Advantose™ FS95 Fructose, SPI Pharma, New Castle, Del.),pregelatinized corn starch (such as Spress® B820, Grain ProcessingCorp., Muscatine, Iowa and Starch 1500®, Colorcon Inc., West Point,Pa.), high density microcrystalline cellulose (such as Avicel® PH-302,FMC Biopolymer, Philadelphia, Pa., Pharmacel® 200, DMV InternationalPharma, Veghel, The Netherlands and Emcocel® HD90, PenwestPharmaceuticals Co., Patterson, N.Y.), direct compressionmicrocrystalline cellulose (such as Avicel™ PH-200, FMC Biopolymer,Philadelphia, Pa., Pharmacel® 102, DMV International Pharma, Veghel, TheNetherlands and Emcocel® 90M and Emcocel® LP200, Penwest PharmaceuticalsCo., Patterson, N.Y.), direct compression silicified microcrystallinecellulose (such as Prosolv SMCC™ 90, Penwest Pharmaceuticals Co.,Patterson, N.Y.), free-flowing grades of dibasic calcium phosphate,dihydrate (such as Emcompress®, Penwest Pharmaceuticals Co., Patterson,N.Y. and Di-Tab®, Rhodia Inc, Cranbury, N.J.) and free-flowing grades ofdibasic calcium phosphate, anhydrous (such as Anhydrous Emcompress®,Penwest Pharmaceuticals Co., Patterson, N.Y. and A-Tab®, Rhodia Inc,Cranbury, N.J.). Most preferred free-flowing diluents are spray-driedlactose and free-flowing lactose monohydrate grades, high density anddirect compression grades of microcrystalline cellulose and silicifiedmicrocrystalline cellulose, spray-dried dextrates, spray-dried andgranular mannitol, spray-dried and coarse sorbitol and free-flowinggrades of dibasic calcium phosphate, dihydrate.

In the present invention, it is more preferred that these diluents beused to reduce the Carr's index and to reduce the angle of internalfriction for azithromycin formulations, particularly in dry blendscontaining an azithromycin drug loading of about 30% or more. The use ofthese diluents is even more particularly preferred when about 20% ormore of the azithromycin particles have a diameter of about 44 micronsor less.

Flavors incorporated in the composition may be chosen from syntheticflavor oils and flavoring aromatics and/or natural oils, extracts fromplants leaves, flowers, fruits, and so forth and combinations thereof.These may include cinnamon oil, oil of wintergreen, peppermint oils,clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil,oil of nutmeg, oil of sage, oil of bitter almonds, and cassia oil. Alsouseful as flavors are vanilla, citrus oil, including lemon, orange,grape, lime and grapefruit, and fruit essences, including apple, banana,pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot,and so forth. The amount of flavoring may depend on a number of factorsincluding the organoleptic effect desired. Generally the flavoring willbe present in an amount of from 0.5 to about 3.0 percent by weight basedon the total tablet weight, when a flavor is used.

For sachets and powders for suspension, the preferred flavoringcomprises a combination of cherry, banana and vanilla flavors as furtherdescribed in Table XIII of U.S. Pat. No. 5,605,889. The teachings ofU.S. Pat. No. 5,605,889, in their entirety, are incorporated herein byreference.

Other excipients and coloring agents may also be added to azithromycintablets. Coloring agents include, but are not limited to, titaniumdioxide and/or dyes suitable for food such as those known as F. D. & C,dyes, aluminum lakes and natural coloring agents such as grape skinextract, beet red powder, beta carotene, annato, carmine, turmeric,paprika, and so forth. A coloring agent is an optional ingredient in thecompositions of this invention, but when used will generally be presentin an amount up to about 3.5 percent based on the total tablet weight.

Dry blends, that are suitable for direct compression tableting, in thepresent invention, include up to about 80 weight percent non-dihydrateazithromycin, from about 10 wt % to about 90 wt % binder, from 0 wt % toabout 85 wt % diluent, from 2 wt % to about 15 wt % disintegrant; andfrom about 0.25 wt % to about 10 wt % lubricant.

In a further embodiment, the dry blend contains up to about 80 wt %azithromycin, from about 2 wt % to about 10 wt % disintegrant, fromabout 0.5 wt % to about 8 wt % lubricant; and from about 0 wt % to about85 wt % diluent.

To prepare the dry blend, the various components may be weighed,delumped and combined except for the lubricating agent. The mixing maybe carried out for a sufficient period of time to produce a homogeneousblend, and then the lubricant may be added. Afterwards, the final mixingmay be carried out. The dry blend may be stored for later use ortableted on suitable equipment.

The components of the dry blend, including the azithromycin and at leastone excipient, may be combined by blending, mixing, stirring, shaking,tumbling, rolling or by any other methods of combining the formulationcomponents to achieve a homogeneous blend. It is preferable that theazithromycin and excipients are combined under low shear conditions in asuitable apparatus, such as a V-blender, tote blender, double coneblender or any other apparatus capable of functioning under preferredlow shear conditions. Lubricant is typically added in the last step.

The invention should not be considered limited to these particularconditions for combining the components and it will be understood, basedon this disclosure that the advantageous properties can be achievedthrough other conditions provided the components retain their basicproperties and substantial homogeneity of the blended formulationcomponents of the formulation is otherwise achieved without anysignificant segregation.

In one embodiment, for preparing the dry blend, the components areweighed and placed, except for the lubricant, into a blending container.Blending is performed for a period of time to produce a homogenous blendusing suitable mixing equipment. The dry blend may be passed through amesh screen to delump the dry blend. The screened dry blend may bereturned to the blending container and blended for an additional periodof time. The lubricant, such as magnesium stearate, may then be addedand the dry blend may be mixed for an additional period of time.

The dry blend is typically free flowing and may be employed in thepreparation of a tablet in standard tableting equipment, or stored forlater use.

Direct compression tablets provided by this invention are solid,intended for oral use, of uniform appearance and with sufficientmechanical strength to withstand possible damage from storage andtransport or a subsequent coating process. In order to prepare a tablethaving suitable properties by direct compression methods, the dry blendmust have good flow properties, good compactability and other suitablephysical characteristics.

The dry blend of the present invention may be employed in thepreparation of a tablet using tableting means, such as, standardtableting equipment known in the industry for gravity fed tabletingprocesses and for equipment having means to force feed thepharmaceutical formulation. In one embodiment, the dry blend is used toprepare tablets on a single station tableting press. Tablets comprisingazithromycin are useful for the treatment of bacterial and protozoalinfections.

In a further aspect of the present invention, an azithromycin tablet ismade according to the following steps. First, azithromycin and at leastone excipient are blended to form a dry blend. A lubricant may be addedto the dry blend during, or subsequent to, the blending of theazithromycin and other excipients. The lubricated dry blend is thencompacted to produce a direct compression tablet.

Optionally, the dry blend may be subjected to a delumping process afterinitial blending. In addition, the lubricated blend may first besubjected to a precompression step on a rotary tablet press prior to thefinal compression step for tablet formation. The lubricated blend mayoptionally be force fed into a die prior to compression.

Suitable dry blends, prior to being lubricated, may comprise up to about80% by weight of azithromycin, from about 10% to about 90% binder, from0% to about 85% filler, from 2% to about 15% disintegrant.

The lubricated blend may comprise from about 0.25% to about 10%lubricant more preferably from about 0.5% to about 3% of lubricant. Theparticular amount of lubricant needed will depend, in part, on theparticular lubricant chosen. More preferably, a suitable lubricated dryblend comprises from about 30% to about 60% azithromycin.

In one embodiment, the direct compression tablet may comprise an amountof lubricant that is greater than about 1% by weight, based on thetablet weight, and less than about 6% by weight, based on the tabletweight. In a further embodiment, the direct compression tablet maycomprise an amount of lubricant that is greater than or equal to about2% by weight, based on the tablet weight, and less than or equal toabout 5% by weight, based on the tablet weight. In an even furtherembodiment, the direct compression tablet may comprise an amount oflubricant that is greater than or equal to about 3% by weight, based onthe tablet weight, and less than or equal to about 5% by weight, basedon the tablet weight.

In one embodiment, the direct compression tablet may comprise an amountof glidant that is less than about 3% by weight, based on the tabletweight. In a further embodiment, the direct compression tablet maycomprise an amount of glidant that is less than about 1% by weight,based on the tablet weight. In an even further embodiment, the tabletmay comprise an amount of glidant that is less than about 0.5% byweight, based on the weight of the glidant. Suitable glidants includemagnesium trisilicate, powdered cellulose, starch, talc, tribasiccalcium phosphate, stearate salts and colloidal silicon dioxide. Mostpreferred glidants are talc, magnesium stearate and colloidal silicondioxide.

Typical compacting techniques for the preparation of a tablet by directcompression utilize a piston like device with three stages in eachcycle 1) filling (adding the constituents of the tablet to thecompression chamber) 2) compaction (forming the tablet) and 3) ejection(removing the tablet). The cycle is then repeated. A representativetablet press is a Manesty Express 20 rotary press, manufactured byManesty Machines Ltd., Liverpool, England, and many others areavailable. The equipment may be gravity fed or it may utilize means toforce feed the lubricated blend into the die. One common method is touse a feed frame, which is equipped with moving paddles to aid infeeding the blend into the die cavities. It should be understood thatcompacting methods and techniques as described in the presentspecification are not limited to any particular equipment.

In one embodiment, a high speed tablet press may be used. In a furtherembodiment, a single station tableting press may be used. Flow of theblend on high speed tablet presses is very important to good weightcontrol of the tablet. The use of a force feeder often improves tabletweight control for poorer flowing blends. Another common feature of highspeed tablet presses is the ability to use precompression.Precompression taps the blend when the die is full with blend before thefinal compression step forms the tablet.

The tablets may be any shape as long as the tablet is in a form that itmay be administered orally and is not prone to capping or exceeds thedesired friability. The tablets may be round, oblong, thick or thin,large or small in diameter, flat or convex, scored or unscored, andimprinted. In one embodiment, the tablets are round, in a furtherembodiment, the tablets are modified oval or modified capsule shaped.

In one embodiment, the tablet may be a modified capsule shape containingabout 250 mgA, about 450 mg total weight. In one embodiment, thedimensions of the aforementioned tablet are 0.26″×0.53″. In a furtherembodiment, the tablet may be a modified oval shape containing about 500mgA, about 900 mg total weight. In one embodiment, the dimensions of thetablet are 0.33″×0.67″. In an even further embodiment, the tablet may bea modified oval shape containing about 600 mgA, about 1070 mg totalweight. In one embodiment, the dimensions of the aforementioned tabletare 0.41″×0.75″. A reference to tablet shapes can be found in FIG. 25,page 51 of the Tableting Specification Manual, fourth edition, publishedby the American Pharmaceutical Association, Washington, D.C., 1995;incorporated herein by reference in its entirety.

In one embodiment, the direct compression tablet may comprise an amountof azithromycin equivalent to about 250 mgA. In a further embodiment thedirect compression tablet may comprise an amount of azithromycinequivalent to about 500 mgA. In an even further embodiment the directcompression tablet may comprise an amount of azithromycin equivalent toabout 600 mgA.

The tablets prepared from the pharmaceutical formulation of the presentinvention exhibit acceptable physical characteristics including goodfriability and hardness. The resistance of a tablet to chipping,abrasion or breakage under conditions of storage and transportationdepends on its hardness and friability.

Friability is a standard test known to one skilled in the art.Friability is measured under standardized conditions by weighing out acertain number of tablets (generally 20 tablets or less), placing themin a rotating Plexiglas drum in which they are lifted during replicaterevolutions by a radial lever, and then dropped approximately 8 inches.After replicate revolutions (typically 100 revolutions at 25 rpm), thetablets are reweighed and the percentage of formulation abraded orchipped is calculated. The friability of the tablets, of the presentinvention, is preferably in the range of about 0% to 3%, and valuesabout 1%, or less, are considered acceptable for most drug and foodtablet contexts. Friability which approaches 0% is particularlypreferred.

If desired, the tablet may be coated. The reasons for coating a tabletmay include masking the taste of the drug, making tablets easier toswallow, protection against chipping during packaging, a barrier formoisture or light to improve product stability, and enhance productappearance or recognition.

The coating process may include the use of a coating solution orsuspension, usually aqueous that has acceptable viscosity for sprayingand properties for it to adhere to the surface of the tablet whenapplied. During the coating process, the coating solution or suspensionis atomized into fine droplets that come into contact with the tablet.As the droplets dry, a film is formed on the tablet which is thecoating. There are several types of coating equipment used to coattablets. One type is the pan coater in which tablets are rotated in apan and coating solution is applied to the tablets as tablets tumble inthe pan. Another coating process involves suspending the tablets in acolumn of air while the coating solution is sprayed onto the tablet(fluid bed process). One example of this is the Wurster column coatingprocess. The tablet may be coated by any known process and the manner ofapplication is not limited to any particular equipment.

The tablet coating(s) may be a white or colored Opadry® (Colorcon, WestPoint Pa.) suspension or a clear Opadry® solution. Alternatively atypical coating formulation would consist of a film forming polymer(s)such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose(HPC), polyvinyl pyrrolidone (PVP) with additional ingredients such asplasticizers, opacifiers, colorants, and antioxidants. Sugar coatingcould also be used.

The dry blends, of the present invention, are suitable for use in thepreparation of a free flowing pharmaceutical formulation. Theformulation may be useful, for example, as a preblend and for use indosage forms such as capsules, sachets and powders for suspension.

Alternatively, pharmaceutical formulations comprising greater than about80% by weight of azithromycin, and having the good flow propertiesdescribed, may be used to prepare other dosage forms, such as capsules.In addition, it might be advantageous to store bulk azithromycin andexcipients separately prior to a direct compression tableting operation.

Azithromycin formulations as defined in this aspect of the invention maycontain bulk drug by itself or bulk drug with one or more excipientssuch as binders, diluents, disintegrants, lubricants, fillers, carriers,and the like, as set forth above.

The formulation may also be used in other applications, including butnot limited to filling a capsule dosage form or any other process thatrequires good flow in the pharmaceutical formulation.

The pharmaceutical compositions of the present invention may be used forthe treatment of bacterial or protozoal infections. The term“treatment”, as used herein, unless otherwise indicated, means thetreatment or prevention of a bacterial or protozoal infection, includingcuring, reducing the symptoms of or slowing the progress of saidinfection.

As used herein, unless otherwise indicated, the term “bacterialinfection(s)” or “Protozoal infection(s)” includes bacterial infectionsand protozoal infections that occur in mammals, fish and birds as wellas disorders related to bacterial infections and protozoal infectionsthat may be treated or prevented by administering antibiotics such asthe compound of the present invention. Such bacterial infections andprotozoal infections and disorders related to such infections include,but are not limited to, the following: pneumonia, otitis media,sinusitis, bronchitis, tonsillitis, and mastoiditis related to infectionby Streptococcus pneumoniae, Haemophilus influenzae, Moraxellacatarrhalis, Staphylococcus aureus, or Peptostreptococcus spp.;pharynigitis, rheumatic fever, and glomerulonephritis related toinfection by Streptococcus pyogenes, Groups C and G streptococci,Clostridium diptheriae, or Actinobacillus haemolyticum; respiratorytract infections related to infection by Mycoplasma pneumoniae,Legionella pneumophila, Streptococcus pneumoniae, Haemophilusinfluenzae, or Chlamydia pneumoniae; uncomplicated skin and soft tissueinfections, abscesses and osteomyelitis, and puerperal fever related toinfection by Staphylococcus aureus, coagulase-positive staphylococci(i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes,Streptococcus agalactiae, Streptococcal Groups C-F (minute-colonystreptococci), viridans streptococci, Corynebacterium minutissimum,Clostridium spp., or Bartonella henselae; uncomplicated acute urinarytract infections related to infection by Staphylococcus saprophyticus orEnterococcus spp.; urethritis and cervicitis; and sexually transmitteddiseases related to infection by Chlamydia trachomatis, Haemophilusducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neisseriagonorroeae; toxin diseases related to infection by S. aureus (foodpoisoning and Toxic shock syndrome), or Groups A, B, and C streptococci;ulcers related to infection by Helicobacter pylori; systemic febrilesyndromes related to infection by Borrelia recurrentis; Lyme diseaserelated to infection by Borrelia burgdorferi; conjunctivitis, keratitis,and dacrocystitis related to infection by Chlamydia trachomatis,Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H.influenzae, or Listeria spp.; disseminated Mycobacterium avium complex(MAC) disease related to infection by Mycobacterium avium, orMycobacterium intracellulare; gastroenteritis related to infection byCampylobacter jejuni; intestinal protozoa related to infection byCryptosporidium spp.; odontogenic infection related to infection byviridans streptococci; persistent cough related to infection byBordetella pertussis; gas gangrene related to infection by Clostridiumperfringens or Bacteroides spp.; and atherosclerosis related toinfection by Helicobacter pylori or Chlamydia pneumoniae. Bacterialinfections and protozoal infections and disorders related to suchinfections that may be treated or prevented in animals include, but arenot limited to, the following: bovine respiratory disease related toinfection by P. haem., P. multocida, Mycoplasma bovis, or Bordetellaspp.; cow enteric disease related to infection by E. coli or protozoa(i.e., coccidia, cryptosporidia, etc.); dairy cow mastitis related toinfection by Staph. aureus, Strep. uberis, Strep. agalactiae, Strep.dysgalactiae, Klebsiella spp., Corynebacterium, or Enterococcus spp.;swine respiratory disease related to infection by A. pleuro., P.multocida, or Mycoplasma spp.; swine enteric disease related toinfection by E. coli, Lawsonia intracellularis, Salmonella, or Serpulinahyodyisinteriae; cow footrot related to infection by Fusobacterium spp.;cow metritis related to infection by E. Coli; cow hairy warts related toinfection by Fusobacterium necrophorum or Bacteroides nodosus; cowpink-eye related to infection by Moraxella bovis; cow premature abortionrelated to infection by protozoa (i.e. neosporium); urinary tractinfection in dogs and cats related to infection by E. coli; skin andsoft tissue infections in dogs and cats related to infection by Staph.epidermidis, Staph. intermedius, coagulase neg. Staph. or P. multocida;and dental or mouth infections in dogs and cats related to infection byAlcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp.,Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella. Otherconditions that may be treated by the compounds and preparations of thepresent invention include malaria and atherosclerosis. Other bacterialinfections and protozoal infections and disorders related to suchinfections that may be treated or prevented in accord with the methodand compositions of the present invention are referred to in J. P.Sanford et al., “The Sanford Guide To Antimicrobial Therapy,” 26thEdition, (Antimicrobial Therapy, Inc., 1996).

The term “effective amount” means the amount of azithromycin which, whenadministered in—the present invention prevents the onset of, alleviatesthe symptoms of, stops the progression of, or eliminates a bacterial orprotozoal infection in a mammal.

The term “mammal” is an individual animal that is a member of thetaxonomic class Mammalia. The class Mammalia includes, for example,humans, monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep,dogs, cats, mice and rats.

In the present invention, the preferred mammal is a human.

Typically, azithromycin, is administered in dosage amounts ranging fromabout 0.2 mg per kg body weight per day (mg/kg/day) to about 200mg/kg/day in single or divided doses (i.e., from 1 to 4 doses per day),although variations will necessarily occur depending upon the species,weight and condition of the subject being treated and the particularroute of administration chosen. The preferred dosage amount is fromabout 2 mg/kg/day to about 50 mg/kg/day.

The azithromycin may be administered orally, or by other known means foradministering azithromycin.

Although the foregoing invention has been described in some detail forpurposes of illustration, it will be readily apparent to one skilled inthe art that changes and modifications may be made without departingfrom the scope of the invention described herein.

Exemplification

The present invention will be further illustrated by means of thefollowing examples. It is to be understood, however, that the inventionis not meant to be limited to the details described therein.

In the following examples, particle size distribution was determinedusing a Malvern Mastersizer S (Malvern Instruments, Worcestershire, UK)with a MS-1-Small Volume Sample Dispersion Unit. This unit allowed forparticle size analysis through a wet sample dispersion step andsubsequent particle size measurements using laser diffraction. Todetermine the particle size, 60 to 75 milliliters of purified water wereadded to the small volume sample dispersion unit and allowed to stir forabout 151 seconds, followed by a 5000 sweep background count.Immediately thereafter, azithromycin bulk was added to this liquid untilan obscuration value of 15-25% was achieved, and measurement of theparticle size was accomplished using 5000 sweeps as exhibited by FIG. 1.

Carr's Compressibility Index of the azithromycin bulk was measured bytaking an initial density of a 15 gram sample in a 100 ml graduatedcylinder. The sample was tapped 2000 times on a VanKel Tap DensityTester (Model 50-1200, Edison, N.J.) and the tapped density of the 15gram sample in the 100 ml graduated cylinder was taken. The procedure isdescribed in Int. J. Pharm. Tech. & Prod. Mfr., 6(3) 10-16, 1985.

Internal angle of friction of the bulk drug was measured by the methoddescribed in “Some Measurements of Friction in Simple Powder Beds”,Hiestand, E. N. and Wilcox, C. J. (J. Pharm. Sci. 57 (1968) 1421).

The shear cell consisted of a layer of powder between two parallel flatsurfaces. The lower surface was fixed and formed the base, while theupper surface (sled) was attached to an actuator which provided a forcein a linear direction parallel to the plane of the surfaces. Anotherforce was applied on top of the sled using weights of known mass. Foreach sample, the test was performed several times using a differentweight on the sled for each test. The force, or resulting shear stress,required to pull the sled across the powder layer increased as theweight on the sled, or resulting normal stress was increased. When thepowder bed yielded during shear, it is said to have failed. Thiscondition represented incipient flow and occurred when the amount offorce needed to move the sled stopped increasing. The data at severalnormal stress levels were plotted as the shear vs. normal stress atfailure. This plot is known as the yield locus, while the angle betweenthe yield locus and the abscissa is known as the Angle of InternalFriction.

The following excipients' trade names are referenced in the examples:

-   Lactose (316 Fast Flo®) was obtained from Foremost Farms, Baraboo,    Wis.-   Microcrystalline cellulose (Avicel® PH-200) was obtained from FMC    Biopolymer, Philadelphia, Pa.-   Croscarmellose sodium (Ac-Di-Sol®) was obtained from FMC Biopolymer,    Philadelphia, Pa.-   Magnesium stearate was obtained from Mallinckrodt, Inc., St. Louis,    Mo.-   Colloidal silicon dioxide was obtained from Cabot Corporation,    Tuscola, Ill.-   Talc was obtained from Whitaker, Clark & Daniels Inc., South    Plainfield, N.J.

Further, in the following examples, the following drug lots wereevaluated:

-   -   Lot 1: Form N, unmilled    -   Lot 2: Form M, unmilled    -   Lot 3: Form A, unmilled    -   Lot 4: Form G, unmilled    -   Lot 5: Form A, milled on Fitzmill with 0.027″ screen, hammers,        low speed    -   Lot 6: Form A, milled on Fitzmill no screen, hammers, high speed    -   Lot 7: Form A, milled on Fitzmill, 0.027″ screen, knives, medium        speed    -   Lot 8: Form A, milled on Fitzmill, 0.020″ screen, knives, high        speed    -   Lot 9: Form M, milled on Fitzmill, 0.033″ rasping screen, bar        rotor, low speed    -   Lot 10: Form F, unmilled    -   Lot 11: Form J, unmilled

EXAMPLE 1 Indices of Tableting Performance

Indices of tableting performance, for several azithromycin forms, wereassessed to identify any mechanical deficiencies or attributes that mayaffect the ability to develop a direct compression tablet formulation ofazithromycin. This assessment was performed in accordance with theprocedures described in “Indices of Tableting Performance” H. E. N.Hiestand and D. P. Smith, Powder Technology 38 (1984] pp. 145-159.

More specifically, the Brittle Fracture Index, BFI, was calculated fromthe ratio of a material's regular tensile strength to its compromisedtensile strength. Strain Index, SI, was determined from the dynamicindentation hardness test. Worst Case Bonding Index was determined byassessing the extent of particle bonding remaining after decompressionassuming a very short compression dwell time and a plastic mechanism ofparticle separation during decompression.

Bulk azithromycin lots 1, 2, 4, 7, 10 and 11 are different crystallineforms, respectively, forms N, M, G, A, F and J. Lots 1, 2 and 4 weremilled with a Fitzmill (Model JT, The Fitzpatrick Co., Elmhurst, Ill.)using a 0.027″ screen and knives at high speed in an attempt to matchthe smaller particle size of Lot 7. Lots 10 and 11 were evaluated as isdue to their relatively small particle sizes.

The results of these assessments are provided, below, in Table 1. TABLE1 Indices of Tableting Performance Brittle Worst Case Fracture BondingStrain Tensile Index Index (BL_(w)) × Index Strength Lot # (BFI) 10²(SI) Mpa #1 Form N 0.05 0.7 0.0044 0.75 #2 Form M 0.10 1.0 0.0048 0.79#4 Form G ND 0.8 0.0043 1.03 #7 Form A 0.10 0.9 0.0044 0.99 #10 Form F0.37 0.9 0.0041 1.62 #11 Form J 0.11 0.7 0.0043 0.69ND = not determined

As shown above, the tableting indices were similar for Lots 1, 2, 4, 7and 11 (Forms N, M, G, A and J). The data suggests that the primarydeficiencies of these materials, in forming tablets by directcompression, are their low to moderate tensile strengths. This may bemanifested as low tablet hardness values. Further, the brittle fractureindices indicate that bonds formed during compression will more likelysurvive decompression when the tablet is ejected from the die.Differences between these lots were not significant. Thus, these lotswould likely have a similar probability of forming a robust directcompression tablet formulation.

Lot 10 (form F), however, appeared to have significantly differentmechanical properties. It has a higher tensile strength value indicativeof forming stronger bonds. The flow properties of Lot 10, however, weresimilar to the other lots having a similar particle size distribution.

In general, a direct compression tablet may be feasible with high drugloading (˜60%) if low brittleness, and good bonding excipients wereused.

EXAMPLE 2 Particle Size Effect

The impact of azithromycin particle size on a direct compression tabletwas evaluated as follows.

Using various lots of azithromycin, direct compression tablets wereprepared from a dry blend of 59.3 wt % azithromycin, 26.9 wt %microcrystalline cellulose as the binder, 8.9 wt % lactose as thediluent, 2.0 wt % croscarmellose sodium as the disintegrant, and 2.9 wt% magnesium stearate as the lubricant.

The ingredients were weighed (except for the magnesium stearate),combined and blended in a low shear blender for 30 minutes. The blendwas passed through a U.S. standard No. 20 or No. 25 mesh screen todelump the blend. The screened blend was returned to the blender andblended for an additional 30 minutes. Prior to the addition of themagnesium stearate, the initial and tapped densities of the blend weredetermined from which a Carr's Compressibility Index for flow wascalculated for the blend. Magnesium stearate was then added to theblend, after which it was blended for an additional five minutes.

The dry blends were compacted on a single station tablet press ManestyF-press (Manesty, Liverpool, United Kingdom) with 0.262″×0.531″ modifiedcapsule shaped tooling. The target tablet weight was 450 milligrams. Thetablets were tested for hardness (kP scale), using a Schleunigerhardness tablet tester (Dr. Schleuniger Pharmatron AG, Solothurn,Switzerland), and for friability (100 rotations/4 minutes) using aVanderkamp Friabulator Tablet Tester (Vankel, Cary, N.C., US). The testresults are provided in Table 2. TABLE 2 Angle of Dry Blend Average Avg.Run Internal Carr's Tablet Tablet Tablet and Friction Index WeightHardness Friability Lot # (°) (%) mg (% CV) (kP) (%) 1 ND 19 451.5 6.60.6  (0.67%, (n = 10) (n = 5) n = 10) 2 ND 25 445.1 6.7 ND (0.32%, (n =3) n = 3) 3 31.0 25 455.3 6.2 1.1  (0.21%, (n = 5) (n = 5) n = 5) 4 30.530 442.4 10.1  0.52 (0.50%, (n = 10) (n = 10) n = 10) 5 31.6 30 455  8.6 0.32 (0.36%, (n = 10) (n = 5) n = 10) 6 32.6 30 452.5 4.1 1.8 (0.90%, (n = 10) (n = 10) n = 10) 7 34.5 34 450.8 12.5  3.67 (2.06%, (n= 5) (n = 5) n = 5) 8 ND 37 No tablets N/A N/A 9 ND 46 No tablets N/AN/A 10 ND 34 No tablets N/A N/AND = Not Determined

Evaluation of the dry blends showed that the unmilled bulk drug (Runs1-4) resulted in acceptable flowing blends having a Carr'sCompressibility Index from 19 to 30 on the tablet press, and tabletswith acceptable weight control, hardness and friability. The lessaggressively milled bulk drug lots (Runs 5-6) also resulted inacceptable flowing blends on the tablet press.

As shown in Table 2, more aggressively milled bulk drug lots (Runs 8 and9) and unmilled bulk drug having a small particle size distribution (Run10) produced poorer flowing blends (Carr's Index of 34 to 46) such thattablets could not be compacted on the Manesty F-press.

A compaction simulator was then used to compress blends containingazithromycin from Lots 7, 8, 9 and 10. The compaction simulator wasdesigned as a single station tablet press in which the compression dwelltime can be adjusted to simulate different types of tablet presses. Inaddition, the compaction simulator was equipped with a mechanicalagitator to assist in filling the tablet die with dry blends to obtain aconsistent tablet weight.

As shown in Runs 11, 12, 13A, 13B, 14A and 14B of Table 2A, poor flowingblends that resulted in unacceptable tablets on the Manesty F-pressbecame acceptable tablets when compressed on the compaction simulator.TABLE 2A Carr's Average Index Applied Tablet Average of dry Upper WeightTablet Tablet Drug blend Compression Mg Hardness Friability Run Lot (%)Force (kN) (% CV) (kP) (%) 11 7 34 5.1 457.2  9.3 0.32 (2.53%, (n = 5)(n = 5) n = 5) 12 8 37 4.0 439.8  6.4 0.73 (1.08%, (n = 5) (n = 5) n =5) 13A 9 46 4.6 428.7 10.6 0.35 (1.15%, (n = 10) (n = 10) n = 10) 13B 946 5.5 426.9 11.9 0.32 (1.44%, (n = 10) (n = 10) n = 10) 14A 10 34 4.2444.9 10.4 0.38 (0.90%, (n = 5) (n = 10) n = 5) 14B 10 34 5.7 456.2 14.10.41 (0.62%, (n = 5) (n = 10) n = 5)

EXAMPLE 3 Drug Loading Effects

The effects of drug loading on the tableting properties of azithromycindirect compression tablets were evaluated as follows. Azithromycintablets were evaluated with low, medium and high drug loadings. The samemanufacturing and testing procedures as set forth in Example 2 wereused.

Pharmaceutical formulations having the following drug loadings were used(percentages are given as % weight): Drug Loading ˜60% ˜45% ˜30%Azithromycin 59.3% 44.5% 29.7% Microcrystalline 26.9% 38.0% 49.2%Cellulose Lactose 8.9% 12.6% 16.2% Croscarmellose 2.0% 2.0% 2.0% SodiumMagnesium 2.9% 2.9% 2.9%. Stearate

Runs 1, 2, 3, 4, 5 and 6, in Table 3, were conducted on a ManestyF-press. The same bulk drug, Lot 8 was used for Runs 1-3, Lot 10 forRuns 4-5, and Lot 11 for Run 6. Runs 7, 8, 9, 10, 11, and 12 in Table 3Awere conducted on the compaction simulator using Lot 8, Lot 10, and Lot11.

Initial evaluation using ˜60% drug loading of the milled bulk drug Lot 8and unmilled Lot 10 resulted in poor flowing blends (Carr's Index of 37and 34 respectively) and poor tablets on the Manesty F-press as shown inTable 2 (Runs 3 and 5). However, low drug loading (˜30%) did improve theflow of the blend and properties as shown in Table 3. TABLE 3 AverageAverage Carr's Drug Tablet Tablet Tablet Drug Index Load Weight mgHardness Friability Run Lot (%) (%) (% CV) (kP) (%) 1 8 33 30 449.7 7.5(max) 0.25 (0.56%, (n = 5) (n = 5) n = 10) 2 8 39 45 457.7 3.7 (max)2.02 (3.38%, (n = 4) (n = 4) n = 8) 3 8 37 60 No No No tablets tabletstablets 4A 10 28 30  441.70 11.5 0.27 (0.95%, (n = 10) n = 10) 4B 10 2830 446.9 20.2 0.31 (0.89%, (n = 10) n = 10) 5 10 34 60 No No No tabletstablets tablets 6A 11 33 30 450.2 10.6 0.20% (0.36%, (n = 2) (n = 3) n =5) 6B 11 33 30 449.0 16.4 0.44% (0.47%, (n = 2) (n = 5) n = 5)

TABLE 3A Average Applied Tablet Average Run/Lot Carr's Upper WeightTablet Tablet % Drug Index Compression mg Hardness Friability Loading(%) Force (kN) (% CV) (kP) (%) 7/8 33 7.2 459.6 12.9 0.21 30% (0.62%, (n= 10) n = 20) 8/8 39 5.8 455.2 10.5 0.13 45% (0.15%, (n = 5) (n = 5) n =15) 9/8 37 4 439.8  6.4 0.73 60% (1.08%, (n = 5) (n = 5) n = 5) 10/10 344.2 444.9 10.4 0.38 60% (0.90%, (n = 5) (n = 10) n = 5) 11/11 33 6.8452.0 18.3 ND 30% (n = 1) (n = 1) 12/11 33 4.4 451.0 12.3 0.35 30%(0.44%, (n = 5) (n = 5) n = 5)ND = Not Determined

As shown, above, in Table 3A, tablets made on the compaction simulatorwere significantly improved in hardness and friability at medium drugload when compared to high drug load when using Lot 8. At low drugloading with Lot 8 or Lot 11, tablets with hardness greater than 12 kPwere achieved using the compaction simulator. Tablets could also be madewith Lot 8 or Lot 10 at the high drug loading using the compactionsimulator. Flow is not a critical parameter for the compaction simulatorsince it uses a mechanical agitator to force the blend into the die.

EXAMPLE 4 Effect of Lubricant

The effect of lubricant levels on the tableting properties of theazithromycin direct compression tablet were evaluated as follows. Directcompression tablet formulations, containing high an low levels ofmagnesium stearate, as a lubricant, were prepared. The high levellubricant formulation contained 59.3 wt % azithromycin, 26.9 wt %microcrystalline cellulose, 8.9 wt % lactose, 2.0 wt % croscarmellosesodium, and 2.9 wt % magnesium stearate. The low level lubricantformulation contained 59.3 wt % azithromycin, 28.3 wt % microcrystallinecellulose, 9.4 wt % lactose, 2.0 wt % croscarmellose sodium, and 1.0 wt% magnesium stearate.

Azithromycin lot 8 was used for the two lubricant level formulations.The same manufacturing and testing procedures, from Example 2, were usedherein.

Evaluation of this bulk drug lot with lubricant at about 3% resulted ina poor flowing blend (Carr's Compressibility Index of 37). Tablets couldnot be made on the Manesty F-press as shown in Table 4. With thelubricant level at 1%, the blend was also poor flowing (Carr'sCompressibility Index of 47) and only unacceptable tablets were made onthe F-press with excessive build up of the material on the punches. Thetablets were very soft with unacceptable low tablet weight (targettablet weight is 450 mg) and poor weight control (% Cv=5.1%). TABLE 4Carr's Index Average Average (Dry Tablet Tablet Tablet Blend) LubricantWeight Hardness Friability Run (%) (%) mg (% CV) (kP) (%) 1 37 3 Notablet No No tablet tablet 2 47 1 418.3 3.3 2.5 (5.1%, (n = 5) n = 10)

As shown in Runs 3 and 4 in Table 4A, poor flowing blends that resultedin unacceptable tablets on the Manesty F-press became acceptable tabletswhen compressed on the compaction simulator. Flow is not a criticalparameter for the compaction simulator since it uses a mechanicalagitator to force the blend into the die. Better tablet friability wasachieved with the 1% lubricant level blend compressed on the compactionsimulator (Run 4). TABLE 4A Carr's Average Index Applied Tablet Average(Dry Lubri- Upper Weight Tablet Tablet Blend) cant Compression mgHardness Friability Run (%) (%) Force (kN) (% CV) (kP) (%) 3 37 3 4.0439.8 6.4 0.73 (1.07%, (n = 5) (n = 5) n = 5) 4 47 1 4.2 462.8 5.8 0.15(0.69%, (n = 10) n = 20)

EXAMPLE 5 Effect of Glidant

The effect of glidant on tableting properties of the azithromycin directcompression tablet were evaluated as follows. Typically, glidants areadded into pharmaceutical formulations to improve flow. As shown in thisexample, addition of glidants into the formulation can improve flow.

Azithromycin direct compression tablets were prepared with glidants toevaluate the effects on the direct compression tablet. The same bulkdrug, lot number 6, was used for all glidant formulations. The samemanufacturing and tablet testing procedures from Example 2 were used inthis example. Runs 1, 2, 3 and 4 were conducted on the Manesty F-press.

The following pharmaceutical formulations were prepared: Run # 1 2 3 4Glidant Formulation wt % Azithromycin 59.3 59.3 59.3 59.3Microcrystalline cellulose 26.8 26.8 26.7 26.9 Lactose 8.9 8.9 8.8 8.9Croscarmellose Sodium 2.0 2.0 2.0 2.0 Colloidal Silicon Dioxide 0.1 —0.3 — Talc — 0.1 — — Magnesium Stearate 2.9 2.9 2.9 2.9

TABLE 5 Carr's Index (Dry Tablet Tablet Blend) weight hardness TabletRun (%) Glidant mg (% CV) (kP) Friability % 1 25 0.10% 455.5 4.6 2.29silicon (0.4%, (n = 5) (n = 7) dioxide n = 5) 2 27 0.10% 449.5 3.6 2.68talc (1.2%, (n = 5) (n = 7) n = 5) 3 28 0.25% 445.2 4.7 Tablets silicon(1.06%, (n = 10) capped dioxide n = 10) 4 30 No 452.5 4.1 1.8  glidant(0.9%, (n = 10) (n = 10) n = 10)

Initial evaluation of the bulk drug lot 6 without glidant, as shown inTable 5, resulted in acceptable blend flow (Carr's Compressibility Indexof 30) on the Manesty F-press. The addition of 0.1% silicon dioxide(Run 1) improved the flow as measured by Carr's Compressibility Indexand the weight uniformity as shown by the lower weight % CV.

EXAMPLE 6 Effect of Sizing

The effect of sieving the bulk drug to selectively remove fines from thebulk azithromycin lot follows.

Lot 8 was screened through a #200 mesh screen using a vibrating sieveanalyzer (Endecott's Octagon 200 test sieve shaker, Endecott, London,England) for 20 minutes at an amplitude setting of 8. The drug retainedon the #200 mesh screen was sieved again using the same screeningprocess. The drug retained on the #200 mesh screen (screened twice) wasused in the following direct compression formulation. The samemanufacturing and testing procedures from Example 2 were used in thisexample. The direct compression tablets had the following composition,by weight:

-   Azithromycin 59.3%-   Microcrystalline Cellulose 26.9%-   Lactose 8.9%-   Croscarmellose Sodium 2.0%-   Magnesium Stearate 2.9%

A better flowing blend (Carr's Compressibility Index of 29) was producedfrom the sieved bulk drug lot. When unsieved Lot 8 was used, the blendwas poor flowing (Carr's Compressibility Index of 37) and tablets couldnot be made (Run 1) on the Manesty F-press as shown in Table 6. Usingthe sieved Lot 8 (Runs 2a and 2b), acceptably hard tablets wereproduced. Runs 2a and 2b were performed with different upper punchcompression settings. Run 2b had a higher setting resulting in greatercompression. The target tablet weight of 450 mg was achieved with goodto excellent weight control. TABLE 6 Carr's Index Average Average (DryBulk Drug Tablet Tablet Blend) Lot Weight Hardness Run (%) Pretreatmentmg (% CV) (kP) 1  37 None, No tablet No tablet unsieved 2a 29 Screened448.4 5.6 twice (1.48%, (n = 5) #200 mesh n = 5) 2b 29 Screened 449.28.3 twice (0.06%, (n = 5) #200 mesh n = 5)

1. A dry blend, used for forming azithromycin tablets by directcompression, comprising: (a) about 1-80%, by weight non-dihydrateazithromycin; and (b) at least one pharmaceutically acceptableexcipient; wherein the Carr's Compressibility Index, of the dry blend,is less than about 34%; wherein said non-dihydrate azithromycin isazithromycin monohydrate hemi-isopropanol solvate or azithromycinmonohydrate hemi-n-propanol solvate. 2-3. (canceled)
 4. A dry blend ofclaim 1 further comprising from about 0.25-10% by weight, of alubricant; wherein the non-dihydrate azithromycin is azithromycinmonohydrate hemi-isopropanol solvate.
 5. A dry blend of claim 1 whereinthe non-dihydrate azithromycin is non-granulated.
 6. (canceled)
 7. A dryblend of claim 1 further comprising about 0.1-85%, by weight, of adiluent.
 8. A dry blend of claim 7 wherein said diluent is from 20-70%,by weight.
 9. A dry blend of claim 8 wherein the diluent is selectedfrom a group consisting of anhydrous lactose, lactose monohydrate,microcrystalline cellulose, silicified microcrystalline cellulose,dextrate, mannitol, sorbitol and dihydrated dibasic calcium phosphate.10. (canceled)
 11. A dry blend of claim 8 wherein the Carr'sCompressibility Index, of the dry blend, is less than about 31%.
 12. Adry blend of claim 8 wherein the Carr's Compressibility Index, of thedry blend, is less than about 28%.
 13. A dry blend of claim 1 furthercomprising from about 2-15%, by weight, of a disintegrant.
 14. A dryblend of claim 13 further comprising: (a) about 2-10%, by weight, of thedisintegrant; and (b) about 0.5-8%, by weight, of a lubricant. 15.(canceled)
 16. A dry blend of claim 1 wherein said lubricant is fromabout 0.5-3%, by weight.
 17. A dry blend of claim 1 wherein saidlubricant is selected from the group consisting of magnesium stearate,calcium stearate, zinc stearate and a mixture of magnesium stearate andsodium lauryl sulfate.
 18. A dry blend of claim 1 further comprising aglidant.
 19. A dry blend of claim 18 wherein the glidant is selectedfrom the group consisting of magnesium trisilicate, powdered cellulose,starch, talc, tribasic calcium phosphate, stearate salts and colloidalsilicon dioxide.
 20. A dry blend of claim 19 wherein the glidant isselected from the group consisting of talc, magnesium stearate andcolloidal silicon dioxide.
 21. A dry blend of claim 1 comprising: (a)about 30-80%, by weight, non-dihydrate azithromycin; (b) about 10-90%,by weight, binder; (c) about 0-85%, by weight, diluent; (d) about 2-15%,by weight, disintegrant; and (e) 0.25-10%, by weight, lubricant.
 22. Adry blend of claim 21 comprising: (a) about 2-10%, by weight,disintegrant; and (b) 0.5-8%, by weight, lubricant.
 23. A dry blend ofclaim 1 wherein the non-dihydrate azithromycin is azithromycinmonohydrate hemi-n-propanol solvate.
 24. (canceled)
 25. A dry blend ofclaim 1 wherein the Carr's Compressibility Index, of the dry blend, isless than about 31%.
 26. A dry blend of claim 1 wherein the Carr'sCompressibility Index, of the dry blend, is less than about 28%.
 27. Adry blend of claim 1 wherein the internal angle of friction, of the dryblend, is less than about 34°.
 28. (canceled)
 29. A dry blend of claim 1wherein the internal angle of friction, of the dry blend, is less thanabout 31°.
 30. (canceled)
 31. A dry blend of claim 1 wherein less thanabout 6% of the total azithromycin particles, by volume as measured bythe Malvern method, have a diameter of 16 μm or less.
 32. (canceled) 33.A dry blend of claim 1 wherein less than about 20% of the totalazithromycin particles, by volume as measured by the Malvern method,have a diameter of 44 μm or less.
 34. A dry blend of claim 33 whereinless than about 14% of the total azithromycin particles, by volume asmeasured by the Malvern method, have a diameter of 44 μm or less.
 35. Adry blend of claim 1 wherein less than about 60% of the totalazithromycin particles, by volume as measured by the Malvern method,have a diameter of 105 μm or less.
 36. A dry blend of claim 35 whereinless than about 50% of the total azithromycin particles, by volume asmeasured by the Malvern method, have a diameter of 105 μm or less.
 37. Adry blend of claim 34 wherein less than about 27% of the totalazithromycin particles, by volume as measured by the Malvern method,have a diameter of 74 μm or less.
 38. (canceled)
 39. A dry blend ofclaim 1 wherein, by volume as measured by the Malvern method, (a) lessthan about 6% of the azithromycin particles have a diameter of about 16μm or less; and (b) less than about 20% of the azithromycin particleshave a diameter of about 44 μm or less.
 40. A dry blend of claim 39wherein less than about 14% of the total azithromycin particles, byvolume as measured by the Malvern method, have a diameter of 44 μm orless.
 41. A dry blend of claim 1 wherein, by volume as measured by theMalvern method, (a) less than about 6% of the azithromycin particleshave a diameter of about 16 μm or less; (b) less than about 20% of theazithromycin particles have a diameter of about 44 μm or less; and (c)less than about 27% of the azithromycin particles have a diameter ofabout 74 μm or less.
 42. A dry blend of claim 41 wherein less than about14% of the total azithromycin particles, by volume as measured by theMalvern method, have a diameter of 44 μm or less.
 43. A dry blend ofclaim 1 wherein, by volume as measured by the Malvern method, (a) lessthan about 6% of the azithromycin particles have a diameter of about 16μm or less; (b) less than about 20% of the azithromycin particles have adiameter of about 44 μm or less; (c) less than about 27% of theazithromycin particles have a diameter of about 74 μm or less; and (d)less than about 60% of the azithromycin particles have a diameter ofabout 105 μm or less.
 44. A dry blend of claim 43 wherein less thanabout 14% of the total azithromycin particles, by volume as measured bythe Malvern method, have a diameter of 44 μm or less.
 45. A dry blend ofclaim 43 wherein, by volume as measured by the Malvern method, (a) lessthan about 14% of the azithromycin particles have a diameter of 44 μm orless; and (b) less than about 50% of the azithromycin particles have adiameter of 105 μm or less. 46-83. (canceled)
 84. A dry blend, used forforming azithromycin tablets by direct compression, comprising: (a)azithromycin monohydrate hemi-isopropanol solvate or azithromycinmonohydrate hemi-n-propanol solvate; and (b) at least onepharmaceutically acceptable excipient.